Regulatory B-cell states in NSCLC immunotherapy resistance: mechanisms, spatial context and translational implications.

Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have improved clinical outcomes, durable benefit is limited by primary and acquired resistance arising from dynamic interactions between tumour cells and the tumour microenvironment. While current models remain largely T cell-centred, accumulating evidence indicates that B-cell states also shape therapeutic response. Here, we propose that regulatory B cells (Bregs) in NSCLC are best understood not as a fixed lineage, but as inducible Breg-associated states that may amplify immunotherapy resistance. We discuss how these states arise under tumour-driven conditions and are further shaped by spatial context, particularly within tertiary lymphoid structures (TLSs) and related immune niches. We further examine how Breg-associated states restrain antitumour immunity and interact with other immunosuppressive populations. This perspective reframes resistance beyond T cell-centric models and supports the development of biomarker-guided, functionally selective, and spatially informed therapeutic strategies.